Nicotine N-glucuronidation relative to N-oxidation and C-oxidation and UGT2B10 genotype in five ethnic/racial groups

Abstract

Nicotine metabolism influences smoking behavior and differences in metabolism probably contribute to ethnic variability in lung cancer risk. We report here on the proportion of nicotine metabolism by cytochrome P450 2A6-catalyzed C-oxidation, UDP-glucuronosyl transferase 2B10 (UGT2B10)-catalyzed N-glucuronidation and flavin monooxygenase 3-catalyzed N-oxidation in five ethnic/racial groups and the role of UGT2B10 genotype on the metabolic patterns observed. Nicotine and its metabolites were quantified in urine from African American (AA, n = 364), Native Hawaiian (NH, n = 311), White (n = 437), Latino (LA, n = 453) and Japanese American (JA, n = 674) smokers. Total nicotine equivalents, the sum of nicotine and six metabolites, and nicotine metabolism phenotypes were calculated. The relationship of UGT2B10 genotype to nicotine metabolic pathways was determined for each group; geometric means were computed and adjusted for age, sex, creatinine, and body mass index. Nicotine metabolism patterns were unique across the groups, C-oxidation was lowest in JA and NH (P < 0.0001), and N-glucuronidation lowest in AA (P < 0.0001). There was no difference in C-oxidation among Whites and AA and LA. Nicotine and cotinine glucuronide ratios were 2- and 3-fold lower in AA compared with Whites. Two UGT variants, a missense mutation (Asp67Tyr, rs61750900) and a splice variant (rs116294140) accounted for 33% of the variation in glucuronidation. In AA, the splice variant accounted for the majority of the reduced nicotine glucuronidation. UGT2B10 variant allele carriers had increased levels of C-oxidation (P = 0.0099). Our data indicate that the relative importance of nicotine metabolic pathways varies by ethnicity, and all pathways should be considered when characterizing the role of nicotine metabolism on smoking behavior and cancer risk.

A Long-Standing Mystery Solved: The Formation of 3-Hydroxydesloratadine Is Catalyzed by CYP2C8 But Prior Glucuronidation of Desloratadine by UDP-Glucuronosyltransferase 2B10 Is an Obligatory Requirement

“…It was previously reported that rabbits may be a particularly useful species for nonclinical studies of drugs that undergo N-glucuronidation in humans (Chiu and Huskey, 1998). However, N-glucuronidation by UGT2B10 on the pyridine moiety of desloratadine cannot be ruled out and has been shown to occur in the case of nicotine and cotinine glucuronidation (Murphy et al, 2014).…”

Progesterone and Postpartum Smoking Relapse: A Pilot Double-Blind Placebo-Controlled Randomized Trial

“…The limit of quantitation for these analyses was 0.4 ng/ml, and the coefficient of variation 6%. 40 Finally, daily data collection at home (EPDS, vaginal bleeding and breastfeeding) was done using EDC.…”

A UGT2B10 Splicing Polymorphism Common in African Populations May Greatly Increase Drug Exposure

“…The relationship of the UGT2B10 rs2942857 alleles, mRNA expression, and RO5263397 and amitriptyline clearance in a panel of hepatocytes from individual African donors revealed that subjects carrying the homozygous genotype CC had poor metabolism and undetectable mRNA. Interestingly, a study on nicotine metabolism in different ethnic groups that was published shortly before our work was submitted for publication (Murphy et al, 2014) has identified the same polymorphic variant of UGT2B10 in African Americans. In other words, two independent studies, ours on a new drug candidate and theirs on nicotine metabolism, although initiated from very different starting points, reached the same finding and they can thus be viewed as supporting and validating each other.…”

“…Similar effects due to SNPs at splice sites resulting in undetectable mRNA species have been observed in other genes, such as TDP-43 (Avendaño-Vázque et al, 2012). In addition, while this article was in preparation, a new study was published, reporting that the same splicing mutation affects nicotine glucuronidation in African Americans (Murphy et al, 2014).…”